Figure 8.

A hypothetical model for the role of EGF signalling and the UFD complex in ageing animals. (A) Larvae maintain protein homoeostasis primarily via chaperones. In larvae, the primary function of the UPS is likely a combination of protein synthesis quality control (e.g. ERAD) and targeted destruction of specific regulatory proteins (e.g. cyclins). Small HSP proteins (brown trapezoid) prevent proteins from unfolding and keep unfolded or misfolded proteins from aggregating. (B) EGF switches adults towards maintaining protein homoeostasis via the UPS. As animals grow older, the number of unfolded and oxidized proteins increases, perhaps in response to a buildup in ROS over time. The EGF/Ras/MAPK pathway becomes activated, triggering a change in gene expression by the EOR-1 and EOR-2 transcription factors. Small HSP proteins are downregulated, resulting in a greater likelyhood that proteins will become unfolded and aggregate. In contrast, SKR-5 and other UPS-associated genes are upregulated, which target oxidized proteins (red elipse) for ubiquitination. In addition, the UFD complex recognizes multiple oligoubiquitinated proteins and adds additional ubiquitins. The resulting polyubiquitinated proteins (red elipse with yellow ubiquitins attached) are substrates for the 26S proteasome, which degrades them. Eventually, even this maintenance system becomes overwhelmed by the misfolded protein load in very old animals, or perhaps damaged itself, contributing to the animal's final decline.